There is now widespread interest in the formulation of therapeutic agents for inhalation. In particular, many efforts have been made to formulate suitable therapeutic agents as dry powders for delivery via inhalers.
Typically, the formulations are produced by drying the active agent in the presence of certain excipients, such as polysaccharides or citrate, to enhance stability during the drying process or in storage.
Insulin is a typical example of a therapeutic agent that can be administered to the lung, by inhalation. As a commercial product, insulin is generally provided in suspension or a solution of low concentration, as a hexamer complexed with zinc Refrigeration is necessary, in order to maintain the stability of such a formulation. Crystalline Zn insulin is stable at neutral pH. The dry powder also requires refrigeration.
CA-A-2136704 discloses a product obtained by spray-drying a medicinal substance such as insulin (among many others) and a carrier. Example 4 discloses spray-drying a clear solution of human insulin soya bean lecithin and lactose
WO-A-9735562 again discloses spray-drying a solution of insulin and a polysaccharide. The aim of this combination is to achieve the preferred size range of spray-dried microparticles, for good lung deposition. In Examples 1 and 3, the insulin solution for spray-drying, prior to combination with polysaccharide, is prepared by dissolving zinc insulin in HCl, and then adding NaOH, to pH 7.2. The solutions for spray-drying respectively contain 25 and 6 mg/ml insulin and at least 5.5/7.2% NaCl, based on the combined weight of insulin plus salt.
WO-A-9524183 is directed primarily to a dry powder that comprises insulin and a carrier material, typically a saccharide, in the form of an amorphous powder of microparticles obtained by spray-drying. In addition the Experimental section compares the properties of such microparticles with and without a saccharide excipient. The insulin solution for spray-drying is prepared by dissolving Zn-insulin in citrate buffer, to pH 6.7 ±0.3, to a solids content of 7.5 mg/ml. The powder is held in a container at 10% RH. The formulation without saccharide has considerably lower bioavailability than those with saccharide. For various reasons, this experiment cannot be reproduced: citrate is a buffer at pH 3.0-6.2, and not at pH 6.7; crystalline insulin will not dissolve in pH 6.2 citrate buffer before or after adjustment to pH 7.4 with NaOH; in any case, no alkali addition is specified.
The presence of citrate in dry powder formulations was believed to be necessary to enhance the stability of the final product (Drug Development and Industrial Pharmacy 1984; 10(3):425-451). However, in many cases, the high citrate concentration dilutes the amount of active agent in The initial feedstock, resulting in low amounts of active for drying.
After the date of this invention, Pikal and Rigsbee, Pharm. Rev. 14(10):1379-87 (1997), reported that freeze-dried amorphous insulin was significantly more stable than crystalline insulin at corresponding water contents from 0 to 15% w/w. The mechanism was unclear, but may have been due to configurational differences between the amorphous and crystalline states, the reactive parts of the protein being in closer proximity in the latter. The formulation reported by Pikal and Rigsbee contains no salt, because such low concentrations of insulin (c. 0.5% w/v) are used that manipulation of the pH is unnecessary
WO95/23613 discloses a spray-dried DNase formulation. The spray-dried product is in a crystalline form, due primarily to a high concentration of salt. It is stated that high concentrations of salt increases the dispersibility qualities of the final product. In Example 1, the final product contains 60% salt compared with 30% of the DNase.
In summary, the prior art discloses various results of interest but of uncertain commercial significance. None of the procedures described above gives a pure insulin product that is stable, or uses a sufficiently concentrated solution for spray-drying, to be suitable as a commercial procedure The most effective procedures invariably suggest that co-spray-drying of insulin and, say, a saccharide is necessary for best results.